This is a competitive renewal application for a bioengineering research partnership (BRP) on breast CT. Over the past 4.3 years, we have developed two breast CT scanners and were the first group to demonstrate the performance of cone beam breast CT in patients, with 94 patients imaged as of January 2007. We also developed the methodology for accurate dose assessment in the pendant breast CT geometry, and have unambiguously shown that excellent quality breast CT images can be produced at radiation levels equal to two view mammography. Good productivity has been achieved in the aims of the previous funding period, with 12 trainees, 14 peer reviewed papers, 11 other papers, 2 chapters, 15 abstracts and 21 invited presentations. In this proposal, we seek to significantly extend the clinical utility of the basic breast CT platform through further technical development combined with clinical evaluation. A new breast CT scanner will be designed and fabricated, utilizing the basic framework of an existing scanner but incorporating a slip ring, pulsed x-rays, and helical acquisition;the system will allow thick fan beam helical scanning for normal operation and cone beam breast imaging for studies using contrast agent injection. In addition to developing new diagnostic imaging modes including contrast kinetic curve assessment, tomosynthesis, breast PET/CT and magnification-mode breast CT, theoretical and numerical analysis methods such as ideal observer assessment and computer aided diagnosis methods are proposed to better understand the fundamental diagnostic potential of breast tomography. We propose further hardware development on the bCT platform so that it will serve as a multifunctional breast cancer analysis and treatment tool, allowing minimally invasive image guided treatment regimes for breast cancer, including robotically guided breast biopsy, radiofrequency ablation, and x-ray ablation. The research plan describes 16 aims in four phases of development (1) new hardware development, (2) analytical tools for improving interpretation and diagnosis, (3) technology development for image guided assessment and treatment of breast cancer, and (4) clinical trials in breast CT diagnosis and treatment. Two nearly identical breast CT scanners will be fabricated and sited at UC Davis and UC San Diego, and patient accrual at two sites will enable the study of over 800 patients, with many cross comparisons. Non-invasive imaging will proceed in Phase II clinical trials, while the minimally invasive studies will be performed in smaller Phase I trials. At the end of this program of research and discovery, breast CT will likely be shown to be a key clinical tool for the diagnosis and treatment of breast cancer.